8, 14-oxido delta4-pregnenes and process therefor



United States Patent 3,082,205 s,14-oxn)o A4-PREGNENES AND PROCESSTHEREFOR Josef Fried, New Brunswick, N.J., assignor to Olin MathiesonChemical Corporation, New York, N.Y., a corporation of Virginia NoDrawing. Filed Sept. 4, 1956, Ser. No. 607,586

- 10 Claims. (Cl. 260-23955) This application is a continuation-in-partof my parent application Serial No. 417,489, filed March 10, 1954, now

US. Patent No. 2,852,511.

This invention relates to the synthesis of steroids and has for itsobjects the provision of: (I) an advantageous process of preparingsteroids of the general formula onion 7 "OH R o l/ w wherein R and R areas above-defined; and (IV) these new steroids, which are useful asintermediates.

The process of this invention essentially comprises interacting A-pregnene-9fl,1 lB-OXidO-l7a,2 l-diol-3,20-dione or a 21-ester thereofwith a strong acid (e.g., perchloric acid and hydrofluoric acid) toyield A -pregnadiene- 11B,17a,2l-triol-3,20-dione or a 21-ester thereof.The resultant steroid may then be esterified by reaction with an acidanhydride or acyl chloride in an organic base to yield the 21-monoester(if a free 21-01 compound is originally formed) or the 11,8,2l-diester.The resultant pregnadiene-ll6,l7a,21-triol-3,20-dione or an llfior 21-monoester or 116,21-diester thereof is then interacted With a peracid(e.g., perphthalic acid) to form a mixture of the two epimeric8,14-epoxides, which are then isolated from the mixture containing thesame. If the free triol or an 11,8- or 2l-monoester thereof is employedas the starting material and a diester is desired as the final product,the initially formed 8,14-epoxide can be acylated in the usual manner,as by treatment with an acyl halide or acid anhydride in an organicbase, to yield the 1lB,21-diester. Conversely, if a diester is employedas the starting material and an epoxide containing free hydroxyl groupsis desired, the initially formed diester can be hydrolyzed in the usualmanner, as by treatment with a base such as potassium carbonate inmethanol, to yield the free 116- and/or 115,21-dihydroxy compound.

Suitable starting materials utilizable in the first step of the processof this invention include A -pregnene-9B,11B-oxido-17a,21-diol-3,20-dione and 21-esters thereof. Among thesuitable ester derivatives may be mentioned those of hydrocarboncarboxylic acids having less than ten carbon atoms (e.g., the lowerfatty acids, such as acetic and propionic acid, and benzoic acid). Inaccordance with this step in the process, one of these startingmaterials is interacted with a strong acid (e.g., perchloric acid andhydrogen fluoride) to yield, inter alia, A-.pregnadiene-l1/8,17a,2l-triol-3,20-dione or a 21-ester thereof. Thisreaction is preferably effected at room temperature or below, optimallyin an inert organic solvent, such as glacial acetic acid or chloroform.

The A -pregnadiene-11p,17a,21-triol-3,2\O-dione or its 2l-ester can thenbe converted to an llfi-ester derivative in the usual manner, as bytreatment with an acyl halide or acid anhydride in a basic organicsolvent, such as pyridine. The preferred acylating agents are the acylchlorides or acid anhydrides of hydrocarbon carboxylic acids having lessthan ten carbon atoms as exemplified by the lower fatty acid anhydridesand benzoyl chloride.

In accordance with the next step of the process of this invention, theresultant A -pregnadiene-11/3,l7u,21- triol-3,20-dione, its Zl-esters,its lie-esters, or its 115,21- diester is interacted with a peracid,such as perphthalic acid. This reaction is preferably conducted in anorganic solvent, such ether or chloroform, in the cold (i.e., at atemperature below room temperature and optimally at about 0 C.).

The 8,14-epoxides of this invention are physiologically active steroidswhich possess anti-inflammatory activity.

Thus, these new steroids of this invention can be administered insteadof, and in the same manner as, hydrocortisone, in the treatment ofrheumatoid arthritis. The dosage for such administration is, of course,dependent on the relative activity of the compound. 7

The following examples are illustrative of the invention (alltemperatures being in centigrade):

EXAMPLE 1 Anhydrous hydrogen fluoride is added to a solution of 15 g. ofA -pregnene-9B,1lfl-oxido-17a,2l-diol-3,20-dione ZI-acetate in 300 ml.of chloroform (contained in a polyethylene vessel provided with a copperinlet tube). During the addition, the solution is maintained in an icebath and agitated by magnetic stirring, until the solution assumes aprominent red color. The inlet tube is then replaced by a (polyethylene)cap, and the reaction is allowed to proceed with stirring for four andone-half hours at 0. Concentrated aqueous sodium bicarbonate solution isthen added until the mixture is slightly alkaline, and the two layersare separated. The now light-yellow chlor-oform solution is washed withwater; and after drying over sodium sulfate, it is evaporated to drynessin vacuo.

The residue (about 17.9 g.) is then taken up in ml.

of hot ethyl acetate, the resulting suspension filtered, and theprecipitate (on the filter) treated as follows.

The ethyl acetate-insoluble material on the filter (about 1.35 g.) isrecrystallized from. acetone. The pure compound has the followingproperties: M.P. about 259-262", with browning; [a] +280 (c., 0.53 in95% ethanol);

A33 239 mu (e=18,000); Ami? 2.94;, 303 5.75;.t, 5.82 4, 6.07 1, 6.11;;

Analysis.[Calculated for C H O (402)]: C, 68.63; H, 7.51. Found(approximately). C, 68.45; H, 7.17.

EXAMPLE 2 A solution of 300 mg. of A-pregnene-9fi,1lfi-oxidol7a,2l-diol-3,20-dione ill-acetate in 30 ml. ofglacial acetic acid and 0.225 ml. of 72% perchloric acid is allowed tostand at room temperature for five minutes. The reaction is stopped bythe addition of dilute sodium bicarbonate and the bulk of the solventremoved in vacuo. The steroids present are extracted with chloroform,the chloroform solution washed with dilute sodium bicarbonate and waterand the solvent removed in vacuo. The crystalline residue (about 340mg.) is recrystallized from 95% ethanol. After removal of a crop ofabout 110 mg. of mixed crystals consisting in part of cortisone acetate,a second crop of about 41 mg. of A -pregnadiene1113,17a,21-triol-3,20-dione 2l-acetate is obtained, which uponrecrystallization from the same solvent melts at about 26l-263 (dec.);

(c., 0.48 in 95% ethanol). Its infrared spectrum is identical with thatof an authentic sample.

EXAMPLE 3 To 10 ml. of hydrogen fluoride is added portionwise at -70over a period of five minutes, 4 g. of A -pregnae-96,116 OXidO17a,21diol-3,20 dione 21-acetate. The resulting deep-red solution is kept atthat temperature for an additional 5 minutes and is then poured intochloroform and ice-cold sodium acetate solution. The chloroform layer iswashed and evaporated to dryness in vacuo. The residue onrecrystallization from acetone furnishes 1.6 g. of A-pregnadiene-11,17a,2l-triol- 3,20-dione 2l-acetate, M.P. about 246-250;

One additional crystallization furnishes analytically pure materialidentical with an authentic sample.

In a similar manner, by following the procedures of Example 1 or 3 butstarting with A -pregnene-9/8,l-1,B oxido-17a,2l-diol-3,20-dione, thereis obtained A pregnadiene-l1B,17a,2l-triol-3,20-dione. If a diester ofan 8,14-epoxide is desired, the 2l-acetate obtained by the procedure ofExamples 1, 2 or 3 can be acetylated or propionated in the ll-positionby treatment with acetic or propionic anhydride in pyridine prior to itsuse in the next step of the process, as illustrated by the followingexample, or, as may fully described hereinafter, the acylation step canbe deferred until the epoxide is formed.

EXAMPLE 4 A -Pregnadiene-115,1 7 (1,21 -Tril-3 ,20-Di one 1 1fl-Propionate 21 -A cetale A1,? 238 my (=18,300); 3.0511. (OH), 572p,5.80;; (propionyl and acetylated side chain), 6.07 6.11 1. (A -3-ketone)AnaIysis.-Calcd. for C H O C, 68.10; H, 7.41. Found: C, 67.93; H, 7.36.

max.

4 EXAMPLE 5 A -Pregnene-8,14-Oxide-1 1 ,8, 1 701,21 -Tri0l-3,20-Di0ne 21-A cetale Titration of 40.4 mg. of A*' -pregnadiene-l16,1711,2l-triol-3,20dione 2 l-acetate in 30 ml. of chloroform with 3 ml. of0.1436 M perphthalic acid in ether at 0 shows an uptake of 1.06 moleequivalents after 17 hours. In a preparative experiment, 340 mg. of thepregnadiene in ml. of chloroform and 25 ml. of ethereal perphthalic acidis stored at 0 for 16 hours. The solution is then extracted with dilutesodium bicarbonate and water, dried over sodium sulfate and the solventremoved in vacuo. The resulting reaction product (about 408 mg.) iscrystallized from acetone and furnishes about 146 mg. of A-pregnene-8,14-oxido-1l,l7u,2l-triol-3,20- dione ZI-acetate (epoxide A21-acetate), melting at about 207-208 (dec.); [a] +243 (c., 0.59 inchloroform);

Rig- 240 mp. (e=16,400); 2.92, 3.05, 5.73, 5.80, till-6.15;;

AnaIysis.Calcd. for C23I'I3007 (418.47): C, 66.01; H, 7.23. Found: C,65.89; H, 6.90.

The mother liquors (238 mg.) obtained in the above procedure aredissolved in 4 ml. of benzene and chromatographed on alumina. Elutionwith chloroform-benzene (1:3, 700 ml.), (1:1, 400 ml.), and 200 ml. ofchloroform furnishes about mg. of the isomeric epoxide (epoxide B21-acetate). Recrystallization from acetone-hexane gives pure materialmelting at about 180 182; [a] +206 (c., 0.58 in chloroform);

Analysis.Calcd. for C H O (418.47); C, 66.01; H, 7.23. Found: C, 66.12;H, 7.01.

Epoxides A and B differ from each other by the orientation of theepoxide ring, one possessing the alpha configuration and the other thebeta configuration.

EXAMPLE 6 A -Pregnene-8J 4-Oxid0-1 1 5,1 70:,21 -Tri0l-3,20-Dione11,3,21-Diacetate (Epoxide A 11,8,21-Diacetate) A solution of 50 mg. ofepoxide A 2l-acetate in 0.5 ml. of anhydrous pyridine and 0.5 ml. ofacetic anhydride is allowed to stand at room temperature overnight.Removal of the reagents in vacuo leaves a residue, which afterrecrystallization from acetone-hexane melts at about 138-140; [a] -{-252(c., 0.46 in chloroform);

Analysis.-Calcd. for C25H320 .H2O 62.75; H, 7.16. Found: C, 62.97; H,6.95.

EXAMPLE 7 Following the procedure of Example 6, but substituting anequal amount of epoxide B 2l-acetate for the epoxide A 21- acetate,there is obtained epoxide B 11,21- diacetate, which melts at about203-205; [a] +207 (c., 0.52 in chloroform);

X311 242 mp (e=l6,600); Milli? 3.06, 5.85, 5.73, 5.80,

ANuiol max.

Analysis.-Calcd. for C H O (460.51): C, 65.20; H, 7.00. Found: C, 65.71;H, 7.26.

Similarly, if other acylating agents are substituted for the aceticanhydride in the procedures of Example 6 or 7, the correspondingll-ester derivative is formed. Thus, propionic anhydride yields anll-propionate and benzoyl chloride yields an ll-benzoate.

The invention may be otherwise variously embodied 7 with the scope ofthe appended claims.

I claim:

1. A compound of the general formula (IJH2OR :0 '---o11 wherein R and Rare selected from the group consisting of hydrogen and the acyl radicalof a hydrocarbon carboxylic acid having less than ten carbon atoms.

2. A -pregnene-8,14-oxido-11;8,17u,21-trio1-3,2O dione 21-acetate.

3. A -pregnene-8,14-oxido-11,B,17ot,21-triol-3,2O dione115,21-diacetate.

4. A process for preparing the compound of claim 1, which comprisesinteracting a steroid of the general formula CH2OR CH2OR wherein R isselected from the group consisting of hydrogen and the acyl radical of ahydrocarbon carboxylic acid having less than ten carbon atoms, whichcomprises interacting a steroid of the general formula CHzOR with astrong acid and recovering the M -steroid 0 formed.

8. The process of claim 7, wherein the steroid reactant is A-pregnene-9fi,11,8-oxido-17a,2l-diol-3,20 dione 21- acetate.

9. The process of claim 8, wherein the strong acid is hydrofluoric acid.

10. A process for preparing a compound of the general formula CHSOR Coirwherein R is selected from the group consisting of hydrogen and the acylradical of a hydrocarbon carboxylic acid having less than ten carbonatoms, which comprises interacting a steroid of the general formulaCH2OR with perchloric acid, and recovering the A -steroid formed.

References Cited in the file of this patent UNITED STATES PATENTS2,606,914 Bernstein Aug. 12, 1952 2,756,179 Fried July 24, 19562,763,671 Fried Sept. 18, 1956 2,813,882 Sar ett Nov. 19, 1957

1. A COMPOUND OF THE GENERAL FORMULA